Quality by Design An Attempt to Jumpstart Innovation Into the

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					Quality by Design: An Attempt to Jumpstart
Innovation Into the Manufacturing Process
           Peter Calcott, Ph.D.
       President, Calcott Consulting

                     GMP in the 21st Century

 • Quality by Design (QbD) is part of Critical
   P th initiative and GMP’ i 21st century
   Path i iti ti     d GMP’s in        t
   driven by FDA
 • Driven by resources
      –   Small increase in FDA staff and dollars
      –   PDUFA restrictions and guarantees
      –   I         i       l
          Increase in supplements t
      –   In spite of slowing of New Molecular Entity

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             What is “Quality by Design”?

 • Quality
      – “Good pharmaceutical quality represents an
        acceptably low risk of failing to achieve the
        desired clinical attributes.”
 • QbD
      – “Means that product and process performance
        characteristics are scientifically designed to
        meet specific objectives not merely
        empirically derived from performance of test
                                              Janet Woodcock (2004)

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  Linking Structure, Function and Controls

 • In a QbD system:
      – The product is designed to meet patient needs and
        performance requirements
      – The process is designed to consistently meet product
        critical quality attributes
      – The impact of starting raw materials and process
        parameters on product quality is understood
      – The process is continually monitored, evaluated and
        updated to allow for consistent quality over time
      – Critical sources of variability are identified and
 • Appropriate control strategies developed

                               Duffy (2007)
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        Quality, Continuous Improvement
             Process (CIP) and QbD
• Proactive approach to continual improvement and
  innovation instead of reactive compliance
• Manufacturing experience and knowledge provides
  opportunity to evaluate and improve processes
• Manufacturing experience and product knowledge
  can be used to establish a “design space”
• Introduction of innovative processes and controls is
  encouraged and will be facilitated
• Robust Pharmaceutical Quality System (PQS) is
  essential to implement scientific risk based change
                           Duffy (2007)
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                QbD and Linkage into ICH

   Q     y     g
 • Quality Design
      – Not testing in but creating quality by
        designing in

      – Linked very much with ICH Q8, 9, 10

      – Heavy into CIP and risk

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                       ICH Q8, Q9 & Q10

 • Q8 – Pharmaceutical development

 • Q9 – Risk based judgment

 • Q10 – Quality Systems – inc CIP

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                     Not all QbD is the Same

 • Principle behind is really to understand what
   makes good products and then make sure
   process is within areas of success to yield
   good product
      – For drugs easily understood
          • Tablet properties, API is very clearly defined
      – For biologics less easily understood
          • Characterisation less than complete,
            immunogenicity, carbohydrate changes
            i          i it     b h d t h
 • From this key parameters that govern Critical
   Quality Attributes (CQA)
 • Process topology / topography
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        QbD can lead to Regulatory Relief

 • Good product CQA           process parameters
       process controls and inputs
 • Process topology/topography understanding
 • Define process controls and inputs
   process parameters        CQA      good product
 • If that done will get regulatory relief and this
   helps industry and regulatory bodies
 • Less number of supplements
      – Simpler and less demanding supplements
      – Less number of and shorter inspections
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                     Regulatory Relief

 • PAS                      PAI/PLI/biennial

 • CBE 0                    decrease length

 • CBE 30                   elimination

 • AR                       reduced cycle

 • NR
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       Safety                          Manufact.
                                       M   f t
       Efficacy                        Process
        (SE)                             (MP)

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  Continuous Improvement Links into QbD


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                                  Duffy (2007)





                 RESEARCH & DEVELOPMENT

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           Two Issues for Success of QbD

 • It is really two fold
        1 – do we understand the process
        landscape? – science
        2 – can we communicate it effectively?
          • Can we tell the story?
          • Is it believed?
          • This is communication and trust

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        Generics, Drugs and Biologics are

 • QbD not the same for generics, drugs and
 • Generics – same compound, specs approval.
   Little process development, just confirming.
   Little understanding of Quality attributes.
 • For generics – science is the issue
 • Changes are quite laborious and dependent
   on the established drug
 • Drugs and biologics more complex approvals
 • Generics Drugs Biologics
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                     Generics Approach

 • Quality by Review (QbR) has made FDA’s
         t ti     l       limited      i
   expectations clearer - li it d experience
 • Guides product and process development
 • Promotes communication among different
   functions within the company
 • Points to the need for good knowledge
   management systems
 • Will and should improve technology transfer

                            Mundkur et al. (2007)
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               Generics Approach (cont.)

 • QbR questions have changed the information
   g        g            p    g generic drug
   gathering and data reporting of g             g
 • Move development activities upfront; more
   product and process understanding reduces
   risk of process scale-up
 • Technical support and technical writers
 • Deficiency questions are science-based and
   are used to re-direct R&D activity for future
                          Mundkur et al. (2007)
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               Generics Approach (cont.)

 • QbR encourages forward thinking of QbD
   elements and principles
 • Define the target of generic product quality
   profile pharmaceutically equivalent to drug
 • Understanding of properties of drug
   substance and product design
 • Understanding of manufacturing process
 • Development report is now more product and
   process design focused

                          Mundkur et al. (2007)
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               Generics Approach (cont.)

    • QbR has changed the quality
      assessment within OGD and has
      generated positive comments from the
    • Office of Generic Drug (OGD) stated
      that QbR is being developed for
      microbiology review and to a certain
      degree, bioequivalence review
                             Mundkur et al. (2007)
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                     Generics Next Steps

•    How much more information and knowledge on
    development activities is needed for filing?
•    M      l it f FDA’s         t ti
     More clarity of FDA’ expectation
•    Developing a risk based approach to achieve
    OGD’s goal of up to 80% CMC supplement reduction
•    Develop metrics beyond the preliminary risk
    assessment strategy proposed by OGD
•    Can post-approval data be evaluated upon review
    or inspection and used for regulatory relief?
•    For some sponsors, additional development work
    (e.g. process) will be needed to fully address QbR
    prior to submission
                             Mundkur et al. (2007)
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 • Science is there
 • Issue is communication and trust
 • Develop NDA that is comprehensive
   and science driven
 • Success story for some innovators

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                     Drugs Next Steps

 • Drugs – processes are simpler than biologics
 • Unit operations
      – API – properties, RM for next step, granulation,
        physical properties, how much variability is
        acceptable for next step – edge of failure
      – Granulated API – tabletting to get quality
      – Tablet properties
      – Controlled delivery devices and prolonged
        release formulations
 • Pfizer has successfully done this – relief from
   inspection for drugs
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         Drugs versus biologics

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                     QbD for Biologics

 • Biologics – much more complex
      – Cell bank to fermentation to Biological
        Drug Substance to vialed product
      – Again – unit operation – RM controls and
        end product for next step
 • QbD is not new for biologics – without it
   we would not have processes.

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                     What are the issues?

 • For biologics, issues surface
      – Lack of complete characterisation – structure
        not 100% known
      – Lack of linkage of Bioactivity measurement
        and chemical potency
      – Significant change in chemistry
        (carbohydrate/glycosylation) yet no change in
        p      y                  g
        potency and also no changes seen in
        chemistry but potency changes seen
      – Changes in immunologic reactions – relevance
      – Pharmacodynamic/Pharmacokinetic
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               The Real Underlying Issue

 • Biologics issue is science, communication
     d trust
   and t t
 • For well characterised products comparability
   protocols step in right direction – partly QbD –
   predicting outcomes
 • QbD – Genentech and others are doing this
   but till       k in
   b t still a work i progress
 • Generic biologics will challenge the paradigm

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        Quality Life Cycle by Kozlowski (2007)

                         Design - Evaluation       Identify – key /
                            Propose                Critical - Ranges &
                   (Desired Attributes/Process)    Parameters
Optimize                                                     (DOE)
                                                     Studies (DOE)
(Continuous                Knowledge Base
                            Q lit Ri k
                            Quality Risks           Confirm
                                                  (Control/ Predict)
                                                    Conformance Lots
  Monitor                                           “Validation Studies”
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                         Take Home Messages

   • QbD is different in industry (generics biologics)
           hil     h leads to
   • QbD philosophy l d t
       – Stronger linkage between departments within
       – Improved success in product approval
       – More robust, efficient commercial operations
       – Decreased production failures
       – Decreased regulatory burden
       – Improved relationship with regulatory bodies
       – Science driven compliance

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             Any questions?

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                       Calcott Consulting

                     Peter Calcott, Ph.D
                President, Calcott Consulting
                         ,                  g
                     Consultant to the Pharmaceutical &
                          Biotechnology Industry

                      Office: 510-527-2662
                      Mobile: 510-585-8256

         Email: peterc@calcott-consulting.com
         Website: www.calcott-consulting.com
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